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Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

ABSTRACT: Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

PROVIDER: PRJNA421927 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6366100.fastq.gz	Fastqsanger.gz
	SRR6366101.fastq.gz	Fastqsanger.gz
	SRR6366102.fastq.gz	Fastqsanger.gz
	SRR6366103.fastq.gz	Fastqsanger.gz
	SRR6366104.fastq.gz	Fastqsanger.gz

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Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma.

Project description:Capicua (CIC) regulates a transcriptional network downstream of the RAS/MAPK signaling cascade. In Drosophila, CIC is important for many developmental processes, including embryonic patterning and specification of wing veins. In humans, CIC has been implicated in neurological diseases, including spinocerebellar ataxia type 1 (SCA1) and a neurodevelopmental syndrome. Additionally, we and others have reported mutations in CIC in several cancers. However, whether CIC is a tumor suppressor remains to be formally tested. In this study, we found that deletion of Cic in adult mice causes T cell acute lymphoblastic leukemia/lymphoma (T-ALL). Using hematopoietic-specific deletion and bone marrow transplantation studies, we show that loss of Cic from hematopoietic cells is sufficient to drive T-ALL. Cic-null tumors show up-regulation of the KRAS pathway as well as activation of the NOTCH1 and MYC transcriptional programs. In sum, we demonstrate that loss of CIC causes T-ALL, establishing it as a tumor suppressor for lymphoid malignancies. Moreover, we show that mouse models lacking CIC in the hematopoietic system are robust models for studying the role of RAS signaling as well as NOTCH1 and MYC transcriptional programs in T-ALL.

| S-EPMC5816173 | biostudies-literature

Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

Project description:Thymic lymphomas were dissected from Cic adult knockout mice or wildtype mice transplanted with Cic adult knockout progenitors. Tissues were snap-frozen in liquid nitrogen until further analysis. RNAs were purified using the AllPrep DNA/RNA mini kit (Qiagen).

2018-01-18 | GSE107915 | GEO

Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

Project description:We isolated RNAs from hematopoietic stem and progenitor cells (HSPCs). We compared two groups of mice: Cicflox/flox (control) and UBC-cre/ERT2; Cicflox/flox (knockout), two weeks post tamoxifen treatment. Following RNA isolation, RNAseq was performed and gene expression profiles were compared between controls and conditional knockouts.

2018-01-18 | GSE103471 | GEO

Inactivation of Capicua in adult mice causes T-cell lymphoblastic lymphoma.

Project description:CIC (also known as Capicua) is a transcriptional repressor negatively regulated by RAS/MAPK signaling. Whereas the functions of Cic have been well characterized in Drosophila, little is known about its role in mammals. CIC is inactivated in a variety of human tumors and has been implicated recently in the promotion of lung metastases. Here, we describe a mouse model in which we inactivated Cic by selectively disabling its DNA-binding activity, a mutation that causes derepression of its target genes. Germline Cic inactivation causes perinatal lethality due to lung differentiation defects. However, its systemic inactivation in adult mice induces T-cell acute lymphoblastic lymphoma (T-ALL), a tumor type known to carry CIC mutations, albeit with low incidence. Cic inactivation in mice induces T-ALL by a mechanism involving derepression of its well-known target, Etv4 Importantly, human T-ALL also relies on ETV4 expression for maintaining its oncogenic phenotype. Moreover, Cic inactivation renders T-ALL insensitive to MEK inhibitors in both mouse and human cell lines. Finally, we show that Ras-induced mouse T-ALL as well as human T-ALL carrying mutations in the RAS/MAPK pathway display a genetic signature indicative of Cic inactivation. These observations illustrate that CIC inactivation plays a key role in this human malignancy.

| S-EPMC5588927 | biostudies-literature

Affymetrix OncoScan SNP data for T-cell lymphoblastic lymphoma

Project description:We performed single nucleotide polymorphism (SNP) array profiling on 9 early T-cell precursor lymphoblastic lymphoma and 15 non-early T-cell precursor lymphoblastic lymphoma cases. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from unstained slides.

2021-03-15 | GSE168884 | GEO

miRNA profiling of pediatric T cell lymphoblastic lymphoma

Project description:miRNA profiling has been performed on primary tumor samples collected at diagnosis from pediatric patients affected by T-cell lymphoblastic lymphoma.

2014-06-10 | GSE55846 | GEO

Capicua-dependent transcriptional changes in adult mouse cerebellum

Project description:Analysis of cerebella from Capicua (Cic) mutant mice and wild-type controls at 28 days of age (P28). Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by expansion of a translated CAG repeat in Ataxin-1 (ATXN1). The transcriptional repressor Cic binds directly to Atxn1 and plays a key role in SCA1 pathogenesis. Two isoforms of Cic, long (Cic-L) and short (Cic-S), are transcribed from alternative promoters. Using embryonic stem cells in which the Cic locus was targeted by an insertion of a genetrap cassette between exon 1 of the Cic-L isoform and exon 1 of the Cic-S isoform, we generated mice that carried this allele and backcrossed these onto a Swiss Webster (CD-1) strain for >6 generations. The resulting Cic-L-/- mice completely lack the Cic-L isoform with ~10% of Cic-S remaining. These data were used to compare with previous microarray data to determine the Cic-depedent pathogenic mechanisms in SCA1. Total RNA from cerebella of wild-type (n=4) and Capicua mutant mice (n=4) at 28 days of age was prepared and labeled according the manufacturer's protocols for the Affymetrix Mouse Gene 1.0 ST Array.

2011-11-07 | E-GEOD-32051 | biostudies-arrayexpress

miRNA profiling of pediatric T cell lymphoblastic lymphoma

Project description:miRNA profiling has been performed on primary tumor samples collected at diagnosis from pediatric patients affected by T-cell lymphoblastic lymphoma. Tumor tissue was frozen at the time of surgery. Mononucleated cells were isolated from pleural effusions upon red blood cell lysis and frozen. The experiment does not include technical replicates.

2014-06-10 | E-GEOD-55846 | biostudies-arrayexpress

RNA-Seq in human T-cell lymphoblastic lymphoma samples and control thymuses

Project description:Precursor T-cell lymphoblastic neoplasms are aggressive haematological neoplasm that most often manifest with extensive marrow and blood affectation (T-cell acute lymphoblastic leukaemia or T-ALL) or less commonly as a thymic mass with limited bone marrow infiltration (T-cell lymphoblastic lymphoma or T-LBL). Here we show data from RNA-Seq in a sample series of T-LBL from Spanish patients.The goal was to determine the levels of expression of coding genes and microRNAs, and to identify all genetic variants including SNVs, indels, and fusion transcripts.

2018-04-25 | GSE109231 | GEO

Mus musculus

Project description:Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma

| PRJNA401747 | ENA